Sj"gren's syndrome (SjS) is an autoimmune, chronic inflammatory disease affecting every population and racial group, and is the second most common connective tissue disease overall. The pathogenesis of autoimmune diseases is complex and, therefore, difficult to study in vitro. The central role in an onset of the SjS is played by T cell-mediated autoimmunity. Unfortunately, there is little known about autoreactive T cells and the role of regulatory T cells in the progression of the SjS, especially that regulatory T cells play a pivotal role in controlling peripheral autoimmunity. One of the major reasons for difficulty to monitor in vivo dynamics of effector or regulatory T cells is high diversity of their TCRs. To study the role of the diversity and specificity of different subsets of CD4+ T cells in pathogenesis of SjS, and how frequency and tissue localization of autoreactive TCRs play the role in onset and progression of the autoimmune disease, we have made mice that possess a mini-repertoire of 12TCRs (TCRmini) on NOD background (NODmini). In this model TCRmini repertoire can be comprehensively monitored at the level of a single T cell clone, and associated with a lineage commitment. Our NODmini mice have polyclonal yet limited repertoire of T cells, develop SjS, and do not develop spontaneous diabetes. The overall goal is to understand how interplay between pathogenic and regulatory T cells influences immunopathology of SjS. We propose to: 1) Identify TCRs contributing to the disease development. Using our retroviral system, we will test pathogenic potential of individual/groups of TCRs and determine their impact on glandular infiltration, autoantibody production and loss of secretory function. 2) Determine defect in regulatory population in their inability to prevent/control the disease using NODmini.Foxp3GFP mouse. We will also determine intrinsic vs. extrinsic factors influencing suppressor defects in Treg cells using C57BL/6.NOD-Aec1Aec2.TCR1-/- (B6.DC.1-/-) mice as a host for adoptive transfer of different proportions of effector and regulatory T cells from health (B6) and autoimmune prone (B6.DC) backgrounds. We hypothesize that an underlying reason for their inability of regulatory T cells to prevent the disease is their inability to sustain regulatory function and/or possible reversal into pathogenic lineage. PUBLIC HEALTH RELEVANCE: The overall goal of this proposal is to understand how interplay between pathogenic and regulatory T cells influences immunopathology of Sj"gren's syndrome. As regulatory T cells have undisputed role in controlling autoimmunity, we will determine how these cells can lose their dominance over pathogenic autoreactive T cells. The results from this proposal should help determine strategies for therapeutic interventions with better efficacy and fewer side effects.